Chronic itch and pain are debilitating conditions that significantly decrease quality of life of millions worldwide and are primary reasons that Americans seek medical attention. Nevertheless, few treatments exist that effectively reduce itch or pain without causing severe adverse effects. This is, in part, because current therapies act on central targets whose mechanisms are poorly understood. Therefore, increasing our knowledge of the regulation of physiologic itch and pain is critical for developing safer and more effective therapies. This proposal aims to reduce this gap, thereby providing insight into the peripheral modulation of itch and pain. Our lab has previously shown that the kappa opioid dynorphin inhibits itch within the dorsal spinal cord. This effect may have been due, at least in part, to presynaptic inhibition via the action of dynorphin on primary sensory afferents in the spinal cord. I now have preliminary data indicating that peripherally selective kappa opioids may inhibit inflammatory itch and pain and reduce thermal sensitivity, suggesting a modulatory role for KOR in conveying these sensory modalities in primary afferent neurons. Therefore, I hypothesize that peripherally selective agonists will act through KOR to inhibit inflammatory itch and pain and reduce thermal sensitivity. This proposal will investigate the functional role of KOR signaling in somatosensory neurons through anatomical, electrophysiological, and behavioral approaches. I will characterize KOR-Cre+ DRG neurons to determine the molecular identity and visualize their peripheral and central projections (Aim 1); use patch-clamp electrophysiology and optogenetic strategies to analyze whether primary afferents express functional levels of KOR and whether these effects occur on peripheral terminals, central terminals, or both (Aim 2); and measure alterations in the behavioral responses to itch and pain-induced stimuli in the presence or absence of peripherally selective kappa opioids (Aim 3). These experiments will elucidate the function of KOR signaling on somatosensory neurons with the potential to identify safer, more effective therapeutic targets for chronic itch and pain.